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Article: The B-MYB transcriptional network guides cell cycle progression and fate decisions to sustain self-renewal and the identity of pluripotent stem cells

TitleThe B-MYB transcriptional network guides cell cycle progression and fate decisions to sustain self-renewal and the identity of pluripotent stem cells
Authors
KeywordsCyclin B1
Myc protein
Octamer transcription factor 4
Polo like kinase 1
Protein b Myb
Issue Date2012
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
PLoS One, 2012, v. 7 n. 8, article no. 42350 How to Cite?
AbstractEmbryonic stem cells (ESCs) are pluripotent and have unlimited self-renewal capacity. Although pluripotency and differentiation have been examined extensively, the mechanisms responsible for self-renewal are poorly understood and are believed to involve an unusual cell cycle, epigenetic regulators and pluripotency-promoting transcription factors. Here we show that B-MYB, a cell cycle regulated phosphoprotein and transcription factor critical to the formation of inner cell mass, is central to the transcriptional and co-regulatory networks that sustain normal cell cycle progression and self-renewal properties of ESCs. Phenotypically, B-MYB is robustly expressed in ESCs and induced pluripotent stem cells (iPSCs), and it is present predominantly in a hypo-phosphorylated state. Knockdown of B-MYB results in functional cell cycle abnormalities that involve S, G2 and M phases, and reduced expression of critical cell cycle regulators like ccnb1 and plk1. By conducting gene expression profiling on control and B-MYB deficient cells, ChIP-chip experiments, and integrative computational analyses, we unraveled a highly complex B-MYB-mediated transcriptional network that guides ESC self-renewal. The network encompasses critical regulators of all cell cycle phases and epigenetic regulators, pluripotency transcription factors, and differentiation determinants. B-MYB along with E2F1 and c-MYC preferentially co-regulate cell cycle target genes. B-MYB also co-targets genes regulated by OCT4, SOX2 and NANOG that are significantly associated with stem cell differentiation, embryonic development, and epigenetic control. Moreover, loss of B-MYB leads to a breakdown of the transcriptional hierarchy present in ESCs. These results coupled with functional studies demonstrate that B-MYB not only controls and accelerates cell cycle progression in ESCs it contributes to fate decisions and maintenance of pluripotent stem cell identity.
Persistent Identifierhttp://hdl.handle.net/10722/169255
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhan, Men_US
dc.contributor.authorRiordon, DRen_US
dc.contributor.authorYan, Ben_US
dc.contributor.authorTarasova, YSen_US
dc.contributor.authorBruweleit, Sen_US
dc.contributor.authorTarasov, KVen_US
dc.contributor.authorLi, RAen_US
dc.contributor.authorWersto, RPen_US
dc.contributor.authorBoheler, KRen_US
dc.date.accessioned2012-10-18T08:47:09Z-
dc.date.available2012-10-18T08:47:09Z-
dc.date.issued2012en_US
dc.identifier.citationPLoS One, 2012, v. 7 n. 8, article no. 42350en_US
dc.identifier.issn1932-6203-
dc.identifier.urihttp://hdl.handle.net/10722/169255-
dc.description.abstractEmbryonic stem cells (ESCs) are pluripotent and have unlimited self-renewal capacity. Although pluripotency and differentiation have been examined extensively, the mechanisms responsible for self-renewal are poorly understood and are believed to involve an unusual cell cycle, epigenetic regulators and pluripotency-promoting transcription factors. Here we show that B-MYB, a cell cycle regulated phosphoprotein and transcription factor critical to the formation of inner cell mass, is central to the transcriptional and co-regulatory networks that sustain normal cell cycle progression and self-renewal properties of ESCs. Phenotypically, B-MYB is robustly expressed in ESCs and induced pluripotent stem cells (iPSCs), and it is present predominantly in a hypo-phosphorylated state. Knockdown of B-MYB results in functional cell cycle abnormalities that involve S, G2 and M phases, and reduced expression of critical cell cycle regulators like ccnb1 and plk1. By conducting gene expression profiling on control and B-MYB deficient cells, ChIP-chip experiments, and integrative computational analyses, we unraveled a highly complex B-MYB-mediated transcriptional network that guides ESC self-renewal. The network encompasses critical regulators of all cell cycle phases and epigenetic regulators, pluripotency transcription factors, and differentiation determinants. B-MYB along with E2F1 and c-MYC preferentially co-regulate cell cycle target genes. B-MYB also co-targets genes regulated by OCT4, SOX2 and NANOG that are significantly associated with stem cell differentiation, embryonic development, and epigenetic control. Moreover, loss of B-MYB leads to a breakdown of the transcriptional hierarchy present in ESCs. These results coupled with functional studies demonstrate that B-MYB not only controls and accelerates cell cycle progression in ESCs it contributes to fate decisions and maintenance of pluripotent stem cell identity.-
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action-
dc.relation.ispartofPLoS Oneen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectCyclin B1-
dc.subjectMyc protein-
dc.subjectOctamer transcription factor 4-
dc.subjectPolo like kinase 1-
dc.subjectProtein b Myb-
dc.titleThe B-MYB transcriptional network guides cell cycle progression and fate decisions to sustain self-renewal and the identity of pluripotent stem cellsen_US
dc.typeArticleen_US
dc.identifier.emailLi, RA: ronaldli@hkucc.hku.hken_US
dc.identifier.emailBoheler, KR: bohelerk@grc.nia.nih.gov-
dc.identifier.authorityLi, RA=rp01352en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0042350-
dc.identifier.pmid22936984-
dc.identifier.pmcidPMC3427317-
dc.identifier.scopuseid_2-s2.0-84865292064-
dc.identifier.hkuros212206en_US
dc.identifier.volume7-
dc.identifier.issue8, article no. 42350-
dc.identifier.isiWOS:000308225500012-
dc.publisher.placeUnited States-

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